tbuckley/cabot-search huggingface dataset:
Abstract 2723: Treatment of gastric cancer cells with tumor treating fields (TTFields) and concomitant FOLFOX
Authors: Naama Flint-Brodsly, Einav Zeevi, Kerem Wainer-Katsir, Hila Fishman, Antonia Martinez-Conde, Eyal Dor-On, Mijal Munster, Yaara Porat, Tali Voloshin, Shiri Davidi, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti
Journal: Cancer Research (2023)

Abstract Background: Gastric cancer, one of the most common types of cancers, is mainly treated with the FOLFOX chemotherapy regimen (oxaliplatin, fluorouracil [5-FU], and leucovorin); yet long-term survival remains poor. Tumor Treating Fields (TTFields) are electrical fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. In several tumor types, the mechanism of action of TTFields included an antimitotic effect and DNA damage induction with impaired DNA damage repair. The current study aimed to examine the efficacy of TTFields for treating gastric cancer cells, and the potential application of TTFields concomitant with FOLFOX. Methods: Human gastric cancer cell lines, AGS and KATO III, were treated with TTFields (intensity of 1.1 and 1.7 V/cm, respectively; frequency of 150 kHz) using the inovitro system. Cell count and colony formation were examined following treatment, and the overall effect calculated by multiplication of the two. RNA sequencing was also performed on samples from control and TTFields-treated cells. Mitotic spindle defects, chromosome miss-localization, and DNA double strand breaks (DSB) formation were examined by fluorescent staining for α-tubulin, phospho-histone 3 (PH3), and phospho-histone H2AX (γH2AX), respectively. Expression of DNA repair proteins was measured using Western Blot. The impact of TTFields with FOLFOX and its individual therapeutic components, oxaliplatin and 5-FU on cell count and clonogenicity was tested. Results: TTFields reduced cell count and the colony forming ability of the cells. Cells treated with TTFields displayed abnormal mitotic figures and increased levels of DNA damage. Expression of DNA repair proteins was downregulated following treatment with TTFields, as evident from RNA and protein levels. Furthermore, TTFields augmented the cytotoxic and clonogenic effects of FOLFOX and its individual therapeutic components, oxaliplatin and 5-FU. Conclusions: TTFields show potential as an effective gastric cancer treatment, with a mechanism of action involving an anti-mitotic effect and DNA damage repair impairment. TTFields may be applied to enhance the efficacy of gastric cancer standard-of-care. Citation Format: Naama Flint-Brodsly, Einav Zeevi, Kerem Wainer-Katsir, Hila Fishman, Antonia Martinez-Conde, Eyal Dor-On, Mijal Munster, Yaara Porat, Tali Voloshin, Shiri Davidi, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Treatment of gastric cancer cells with tumor treating fields (TTFields) and concomitant FOLFOX [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2723.
Abstract 4193: N-NOSE technology based on <i>C. elegans</i> olfaction. Multi-cancer early detection with high sensitivity using urine. Pancreatic-cancer-specific early detection with high sensitivity using urine
Authors: Eric Di Luccio, Takaaki Hirotsu
Journal: Cancer Research (2023)

Abstract N-NOSE (Nematode Nose) is a cancer screening test based on the chemotactic characteristics of the nematode C. elegans. C. elegans shows avoidance of the urine of healthy individuals while displaying a chemotactic attraction toward the urine of patients with 15 types of cancer (stomach, colon-rectum, lung, breast, pancreas, liver, prostate, uterus, esophagus, gallbladder, bile duct, kidney, urinary bladder, ovary, oropharynx) rendering N-NOSE a primary multi-cancer screening test. N-NOSE has a high sensitivity of 87.5% and 90.2% specificity, on average, from early stage 0-I. N-NOSE is non-invasive because it relies on a urine sample and is affordable (JPY 13,800, ~USD 100).N-NOSE by Hirotsu Bio Science has been available in Japan since late 2020 and is a commercial hit with over 250,000 screenings performed, rapidly increasing. In this presentation, we outline the N-NOSE technology and business in Japan. We review N-NOSE clinical research and critical findings compared to competitors that highlight its excellent performance as a non-invasive primary cancer screening for early detection. N-NOSE is a multi-cancer early detection test. Next, we introduce an evolution of N-NOSE for identifying the cancer type. Pancreatic cancer is the 12th most common cancer worldwide but remains one the deadliest cancer with a 5-year relative survival rate at only 11%, all stages combined. An affordable, non-invasive, and highly sensitive early-stage pancreatic cancer screening test is sorely needed. As an evolution of N-NOSE we genetically engineered C. elegans by knocking out in AWC olfactory neurons a specific olfactory receptor (GPCR), triggering a chemotactic response particular to the only pancreatic cancer urine specimen at an early stage. In this study, we outline, for the first time, the critical discovery of cr-4 GPCR in AWC, which is crucial for a specific chemotaxis response to the urine of patients with pancreatic cancer. Next, we briefly conclude by outlining the link between N-NOSE primary cancer screening followed by N-NOSE cancer type identification, effectively completing the whole cancer screening and identification process in a non-invasive way. Citation Format: Eric Di Luccio, Takaaki Hirotsu. N-NOSE technology based on C. elegans olfaction. Multi-cancer early detection with high sensitivity using urine. Pancreatic-cancer-specific early detection with high sensitivity using urine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4193.
Abstract 5149: Age-associated remodeling of anti-tumor T cell immunity and metabolism
Authors: SeongJun Han, Peter Georgiev, Alison Ringel, Arlene Sharpe, Marcia Haigis
Journal: Cancer Research (2023)

Abstract Aging results in remodeling of T cell immunity and is associated with poor clinical outcome in age-related diseases such as cancer. Amongst the hallmarks of aging, changes in host and cellular metabolism are critically involved in the development, maintenance, and functional responses of T cells. Although metabolic perturbations impact anti-tumor T cell responses, the link between age-associated metabolic dysfunction and anti-tumor immunity remains unclear. First, we utilized B16, MC38 and E0771 tumor-bearing young (2-4 months) and aged (18-24 months) C57BL/6 mice to examine the effects of aging on tumor growth. Aged mice exhibited accelerated tumor growth in B16, MC38 and E0771 tumor models. Flow cytometric analyses of tumor infiltrating lymphocytes (TILs) revealed distinct changes in CD8+ T cell population, decreased activation status and tumor-specificity in aged mice. Consistent with these findings, CD8+ T cells functionally played a limited role in controlling tumor growth in aged mice. Here, we will explore the mechanisms of age-associated metabolic dysfunction in T cells and its implications in anti-tumor immunity. As the average life expectancy continues to increase, understanding the interplay between age-related metabolic reprogramming and maladaptive T cell immunity will be instrumental in the development of novel therapeutic strategies for older patients. Citation Format: SeongJun Han, Peter Georgiev, Alison Ringel, Arlene Sharpe, Marcia Haigis. Age-associated remodeling of anti-tumor T cell immunity and metabolism. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5149.
Abstract 6174: ATX-101, a peptide drug targeting PCNA, enhances the effect of gemcitabine in liposarcoma and leiomyosarcoma
Authors: Elgilda Musi, Tahir Sheikh, Matthew Ingham, Sminu Bose, Gary K. Schwartz
Journal: Cancer Research (2023)

Abstract Soft tissue sarcomas are heterogeneous mesenchymal neoplasms and account for 1% of all cancers in adults. Over 50 sarcomas subtypes have been classified and many have very limited treatment options which include surgery, chemotherapy and radiation. Two of the most common sarcomas are liposarcoma and leiomyosarcoma which are often treated with chemotherapies such as doxorubicin, dacarbazine and gemcitabine with low response rates. There is now more than ever an urgent need for new therapies for sarcoma. PCNA (Proliferating Cell Nuclear Antigen) is considered to be a key regulator of DNA and cell cycle control. In addition, it has been implicated to have roles in metabolism, cellular signaling and some immunological functions. PCNA forms complexes with proteins bearing a novel PCNA-interacting Peptide Motif called APIM (AlkB homolog 2 PCNA Interacting Motif). This binding usually occurs during stress responses such as those achieved during cancer therapy or cancer development. By preventing stress proteins from repairing or defending themselves, cancer therapies can be made more effective. We examined the in vitro effects of ATX-101, a PCNA-APIM protein interaction blocking peptide, on liposarcoma cell lines LS141, DDLS, SW872, 93T449 and 94T778 and leiomyosarcoma cell lines SK-LMS, SK-UT1 and SK-UT-1B. Cell survival, as measured by cell proliferation assays, indicated IC50s of 7.5-15µM with ATX-101. Enhanced combination effects with ATX-101 and chemotherapies such as doxorubicin, irinotecan and gemcitabine were also observed by proliferation assay. Synergism, with ATX-101 and gemcitabine, was indicated with SynergyFinder analysis. Cell cycle changes exhibited increases of S and G2 phases when treated with ATX-101 and gemcitabine. This correlated with increase of cell cycle proteins, cyclin B1 and cyclin A2. Western blot observations included increase of apoptotic marker, cleaved caspase 3, and DNA damage marker, pH2A.X. In addition, immunofluorescence assay showed increasing pH2A.X with ATX-101 and gemcitabine. In vivo studies revealed ATX-101 enhanced gemcitabine decrease of tumor volume in leiomyosarcoma cell line xenograft, SK-UT1. Tumor target inhibition by western blot showed increased pH2A.X and cleaved PARP along with decreased RAD51 API protein with combination treatment. Taken these observations and results, there is strong evidence of combining gemcitabine with ATX-101 in liposarcoma and leiomyosarcoma. Citation Format: Elgilda Musi, Tahir Sheikh, Matthew Ingham, Sminu Bose, Gary K. Schwartz. ATX-101, a peptide drug targeting PCNA, enhances the effect of gemcitabine in liposarcoma and leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6174.
Abstract 2612: Mutational pattern of SWI/SNF pathway genes in lung adenocarcinoma patients reveal uneven correlation with immunotherapy sensitivity
Authors: Haimeng Tang, Hua Bao, Xue Wu, Yang Shao
Journal: Cancer Research (2023)

Abstract Background: The search for prognostic biomarkers indicating sensitivity to immunotherapy in lung adenocarcinoma patients have zeroed in on genes in the SWI/SNF pathway. However, the mutational profiles of the relevant key genes on this pathway have not been clearly defined, and no comparisons have been conducted on whether mutations in these genes provide the same predictive value in lung cancer patients. Methods: In this study, statistical analysis of clinical factors, tumor mutation burden, chromosomal instability, and co-appearing alterations of 5 key genes on the SWI/SNF pathway was conducted for 4344 lung adenocarcinoma samples. Two independent online cohorts (N = 1661 and N = 576) were used to supplement the analysis with survival and RNA-Seq data, respectively. Results: ARID mutations were found to be more prominent in males under the age of 60 than any other clinical group, while no significant differences exists for SMARC-mutant groups. Mutational burden and chromosomal instability analysis showed that patients with either ARID family mutations (including ARID1A, ARID1B, or ARID2 mutations) or SMARC family mutations (including SMARCA4 or SMARCB1 mutations) display different sample-level metrics than patients with wild-type samples (TMB: ARID v WT: p&amp;lt;2.2X10-16, SMARC v WT: p&amp;lt;2.2X10-16; CIN: ARID v WT: p=1.8X10-5, SMARC v WT: p=0.027). Additionally, both mutant groups have a higher proportion of transversions than transitions, while the ratio is more equal for wild-type samples. Survival analysis shows that patients with ARID mutations were more sensitive to immunotherapy treatment than wild-type and SMARC-mutated patients (p &amp;lt; 0.001 and p=0.013, respectively), and multivariate cox analysis reveals that presence of ARID mutations is likely the main cause. Furthermore, we observed higher expression of genes on the MTOR1C signaling pathway and the unfolded protein response pathway in the SMARC-mutated group in comparison to the ARID-mutated group, both of which have been reported to increase resistance to immunotherapy. Conclusions: In summary, the mutational landscape of 5 major SWI/SNF pathway genes were classified. The research presented also shows that mutations in the ARID gene family, including ARID1A, ARID1B, and ARID2, are primarily responsible for the sensitive response to immunotherapy treatment in patients with SWI/SNF mutant lung adenocarcinoma. Citation Format: Haimeng Tang, Hua Bao, Xue Wu, Yang Shao. Mutational pattern of SWI/SNF pathway genes in lung adenocarcinoma patients reveal uneven correlation with immunotherapy sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2612.
Abstract 400: TIP60-mediated regulation of DNp63a is associated with cisplatin resistance
Authors: Akshay Hira, Andrew J. Stacy, Jin Zhang, Mike Kemp, Madhavi P. Kadakia
Journal: Cancer Research (2023)

Abstract About 5.4 million basal and squamous cell skin cancers are diagnosed each year in the US. The chemotherapeutic drug, Cisplatin is often used to treat squamous cell carcinoma (SCC) patients, but low response rates and disease recurrence is common. ΔNp63α, a member of the p53 family of transcription factors, is overexpressed and considered oncogenic in non-melanoma skin cancer where it regulates cell survival, promotes proliferation and inhibits cell apoptosis. ΔNp63α has also been shown to promote resistance to cisplatin by transcriptionally regulating several DNA damage response (DDR) genes. A previous study from our lab showed that the histone acetyltransferase (HAT) TIP60 promotes SCC proliferation by positively regulating ΔNp63α protein levels in manner dependent on the catalytic activity of TIP60. This finding suggested that TIP60 may contribute to the failure of platinum-based drugs in SCC and led us to hypothesize that TIP60-mediated acetylation of ΔNp63α regulates its stability and transcriptional activity to promote chemoresistance. Silencing endogenous TIP60 led to a decrease in ΔNp63α transcript and protein levels in multiple SCC cell lines, indicating the positive regulation of ΔNp63α by TIP60 is not cell-line specific. Further, TIP60 levels positively correlated with ΔNp63α stability, protein levels and cisplatin resistance. Stable expression of TIP60 or ΔNp63α individually promoted resistance to cisplatin and reduced cell death, whereas loss of ΔNp63α and TIP60 induced G2/M arrest, increased cell-death and sensitized cells to cisplatin. Moreover, pharmacological inhibition of TIP60 reduced acetylation of ΔNp63α and sensitized resistant cells to cisplatin. Finally, we demonstrated that ΔNp63α and TIP60 levels positively correlated with DNA repair capacity and negatively correlated with cisplatin-DNA adduct formation. Silencing of either TIP60 or ΔNp63α enhanced cisplatin-DNA adduct formation and significantly reduced expression of genes involved in DDR. Taken together, our data indicate that TIP60-mediated stabilization of ΔNp63α increases cisplatin resistance and provides critical insights into the mechanisms by which ΔNp63α confers cisplatin resistance through regulation of genes involved in DNA damage repair. Our findings suggest that inhibition of TIP60 may be therapeutically advantageous in overcoming cisplatin resistance in SCC other epithelial cancers. Citation Format: Akshay Hira, Andrew J. Stacy, Jin Zhang, Mike Kemp, Madhavi P. Kadakia. TIP60-mediated regulation of DNp63a is associated with cisplatin resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 400.
Abstract 1922: PhyloFrame: A machine learning framework for ancestry agnostic disease signatures
Authors: Leslie A. Smith, James A. Cahill, Kiley Graim
Journal: Cancer Research (2023)

Abstract Rapid advancements in genomic sequencing technologies have catalyzed the molecular identification and treatment of previously elusive diseases. Despite these genomic advancements, disparities in precision medicine access and data have resulted in disparate impacts on different socioeconomic groups. Many of the gold standard datasets largely exclude minority populations, compounding their exclusion from medical research. This has resulted in a restricted understanding of cancer and other complex diseases. We demonstrate the effects of ancestral bias in gold standard genomics datasets through ancestral analysis of cancer-related genes in the Cancer Gene Census, spanning 17 ancestral populations. Additionally, we present a machine learning framework, PhyloFrame, that incorporates population genomics data to correct for ancestral bias by creating disease signatures representative of all ancestries. Our ancestral analysis results show that while a majority of the current cancer-related genes in the Cancer Gene Census have below average mutation frequency in non-European populations, there are peaks of ancestrally enriched mutations in ancestry-specific genes related to cancer, which can be targeted using PhyloFrame. PhyloFrame prioritizes gene expression from the cancer genes with high frequency mutations in a given human population in order to capture genes driving disease in each ancestry. It builds on existing disease gene signatures and big-data functional interaction networks to identify ancestry-relevant genes related to a disease, outputing an ancestry-agnostic disease signature. We test PhyloFrame on TCGA cancers with diverse patient populations, such as breast cancer, and compare PhyloFrame's disease signature output to the disease signature output of elastic net runs on cancer samples from a single ancestry. Our results demonstrate that the incorporation of ancestral information allows PhyloFrame to recapitulate disease signatures trained on only one ancestry in a dataset with individuals from many unquantified ancestries. With the incorporation of ancestral information, PhyloFrame is able to create disease signatures with genes pertinent to each ancestral population, even when individuals from those populations are not included in the training data. This work offers a quick and cheap alternative to the mass sequencing that would be required to capture disease-driving genes in minority populations in hopes to contribute to equitable representation in medical research. Citation Format: Leslie A. Smith, James A. Cahill, Kiley Graim. PhyloFrame: A machine learning framework for ancestry agnostic disease signatures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1922.
Abstract 237: Coincidence of InDels with missense mutations: 0, 1 or 2 artifacts
Authors: Kelly E. Craven, Catherine G. Fischer, LiQun Jiang, Aparna Pallavajjala, Ming-Tseh Lin, James R. Eshleman
Journal: Cancer Research (2023)

Abstract The purpose of this study was to explain a serendipitously discovered next generation sequencing (NGS) artifact. While reviewing clinical cases, we found a case of a large deletion that also contained multiple missense mutations. This phenotype was unknown to several molecular pathologists in our group. We reviewed 46 clinical cases with short insertions or deletions (InDels) (1-30 bases) or FLT3 internal tandem duplications (ITDs) (6-183 bases) of solid or hematologic malignancy processed with a clinical NGS assay and identified misaligned reads, ranging from 3 to 100% of reads showing mismapped bases. Reads that straddled the InDel with sufficient numbers of bases on both sides were correctly anchored both upstream and downstream of the InDel, and were called correctly. However, reads that ended in the middle of the InDel were incorrectly mapped onto the deletion, thereby producing artifactual missense mutations. The frequency of mismapped bases increased with InDel size, and the VAF of the InDel can be markedly underestimated. The ratio of forward to reverse reads was commonly skewed for the mismapped base compared to the ratio for the wildtype base at that position. ABRA2 was able to correct 41 to 100% of the reads with mismapped bases and led to absolute increases in the VAF from 1 to 61% along with correction of all of the SBSs except for two cases. Knowledge of the various artifacts commonly seen in next generation sequencing is essential to safely sign out molecular pathology cases. Citation Format: Kelly E. Craven, Catherine G. Fischer, LiQun Jiang, Aparna Pallavajjala, Ming-Tseh Lin, James R. Eshleman. Coincidence of InDels with missense mutations: 0, 1 or 2 artifacts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 237.